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Adjuvant chemotherapy improves survival after resection of stage 1 ovarian cancer
CANCER TREATMENT REVIEWS (2005) 31, 323–327
www.elsevierhealth.com/journals/ctrv
EVIDENCE-BASED ONCOLOGY
Adjuvant chemotherapy improves survival after resection of stage 1 ovarian cancer Abstracted from: Elit L, Chambers A, Fyles A, Covens A, Carey M, Fung MFK. Systematic review of adjuvant care for women with stage I ovarian carcinoma. Cancer 2004;101:1926–1935.
Background Approximately one third of women with ovarian cancer have stage 1 disease, which is confined to the ovary. Adjuvant chemotherapy is the standard procedure for women with higher stage disease, but there is uncertainty about the clinical effectiveness of adjuvant therapy for stage 1 disease.
ogy proceedings from 1997 to 2003 and of reference lists of retrieved papers were also carried out.
Inclusion criteria
Objective
Randomised controlled trials (RCTs) comparing two or more adjuvant therapies in women with resected stage 1 ovarian cancer (or including at least 60% of women with stage 1 cancer) were included. Non-English studies were excluded.
To assess the clinical effectiveness of adjuvant therapy in women with resected stage 1 ovarian cancer.
Main outcomes Overall survival; disease-free survival; adverse events.
Method Systematic review with meta-analysis.
Search strategy MEDLINE, CANCERLIT, The Cochrane Collection, Physician Data Query, Canadian Medical Association, and National Guidelines Clearinghouse databases from 1965 to April 2004. Hand searches of American Society of Clinical Oncol-
Main results The review identified 13 RCTs in women with resected stage I ovarian cancer. However, only two RCTs used optimal methods of surgical staging. Adjuvant chemotherapy. Seven RCTs compared adjuvant chemotherapy versus no adjuvant chemotherapy, and five were meta-analysed. Adjuvant chemotherapy significantly reduced death and
0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.04.003
324
Evidence-based Oncology
disease recurrence compared with no treatment (Evidence Profile: Benefits 1). Two RCTs published as abstracts found no significant difference between different chemotherapy schedules or administration methods (Evidence Profile: Benefits 2). Adjuvant radiotherapy. One small and potentially underpowered RCT found no difference in survival between adjuvant radiotherapy and no treatment. However, one RCT found that adjuvant radiotherapy increased disease recurrence. Adjuvant chemotherapy vs. adjuvant radiotherapy. Three RCTs found no significant difference in survival between adjuvant chemotherapy and pelvic radiotherapy or whole abdominopelvic radiotherapy. One of the RCTs found that adjuvant melphalan significantly increased recurrence-free survival compared with adjuvant pelvic radiotherapy. Four RCTs found no significant difference in overall survival or disease-free survival between
adjuvant chemotherapy and radioactive chromic phosphate. Adverse events and treatment related mortality. Data on adverse events and treatment related mortality were limited and did not allow for comparison across studies (Evidence Profile: Harms).
Authors’ conclusions Overall, adjuvant chemotherapy improves survival and reduces recurrence in women with stage 1 ovarian cancer. However, the extent to which this finding is generalisable to women receiving optimal surgical staging is unclear. There was insufficient evidence on which to draw conclusions on the benefits of adjuvant radiotherapy.
Evidence Profile: Benefits 1 Outcome Death Disease recurrence
Absolute risk Adjuvant chemotherapy
No treatment
95/630 (15.1%) 129/630 (20.5%)
127/621 (20.5%) 181/615 (29.4%)
Relative risk
95% CI
P-Value
0.74 0.70
0.58 to 0.94 0.58 to 0.86
0.01 0.0004
Meta-analysis of five RCTs.
Evidence Profile: Benefits 2 Comparison Different types of chemotherapy Paclitaxel + carboplatin: 3 cycles vs. 6 cycles (n = 321) Intravenous vs. oral chemotherapy (n = 96) Radiotherapy vs. no radiotherapy Pelvic RT vs. no RT (n = 41) Pelvic RT vs. no RT (n = 52) Chemotherapy vs. radiotherapy Cisplatin vs. WAR (n = 70) Chemotherapy vs. pelvic RT (n = 65) Melphalan vs. pelvic RT (n = 57) Cyclophosphamide + cisplatin vs. 32P (n = 251) Cisplatin vs. 32P (n = 161) Cisplatin vs. 32P (n = 340) Meplhalan vs. 32P (n = 141) 32
5-Year disease free survival
P-Value
5-Year overall survival
P-Value
73% vs. 81%
Not significant
NR
NR
NR
Not significant
NR
Not significant
NR 70% vs. 83%
NR P < 0.05
NR NR
Not significant NR
74% vs. 50% NR 94% vs. 70% 70% vs. 76%a
P = 0.07 NR P < 0.05 Not significant
71% vs. 53% 74% vs. 87% NR 81% vs. 79%
P = 0.16 Not significant NR Not significant
NR 79% vs. 82% 80% vs. 80%
NR Not significant Not significant
81% vs. 79% NR 81% vs. 78%
Not significant NR P = 0.48
P: radioactive chromic phosphate; NR: not reported; RT: radiotherapy; WAR: whole abdominopelvic radiotherapy. 10-year recurrence free survival.
a
Evidence-based Oncology
325
Evidence Profile: Harms Comparison
Adverse events
Chemotherapy vs. no chemotherapy Melphalan vs. no CT (n = 81) Mild to moderate haematologic and gastrointestinal toxicity with melphalan. Melphalan associated with myelosuppression (79%), and severe thrombocytopenia (18%) Chemotherapy vs no CT NR (n = 75) Different types of chemotherapy Paclitaxel + carboplatin: Greater toxicity (anaemia, 3 cycles vs. 6 cycles (n = 321) granulocytopenia, neurotoxicity) with 6 cycles of chemotherapy (no further data provided) Intravenous vs. oral Greater toxicity chemotherapy (n = 96) (myelosuppression, GI sequelae, hair loss) with intravenous chemotherapy (no further data provided) Radiotherapy vs. no radiotherapy Pelvic RT vs. no RT (n = 41) Radiotherapy was associated with myelosuppression (66%), bowel cramps/diarrhoea (64%), nausea/ vomiting (54%) and neutropenia (45%) Chemotherapy vs. radiotherapy Cisplatin vs. WAR (n = 70)
Chemotherapy vs. pelvic RT (n = 65) Melphalan vs. pelvic RT (n = 57) Cyclophosphamide + cisplatin vs. 32P (n = 251)
Cisplatin vs.
32
P (n = 161)
Cisplatin vs.
32
P (n = 340)
Meplhalan vs.
32
32
P (n = 141)
Treatment-related mortality NR
No treatment-related mortality
NR
NR
1 surgery-related death in radiotherapy group (no further data provided)
Grade 3 or 4 nausea/vomiting: 71% vs. 14% (P < 0.01). No other Grade 3 or 4 toxicities with chemotherapy. WAR was associated with Grade 3 or 4 diarrhoea (28%) and enteritis (14%) NR
NR
NR Chemotherapy associated with Grade 3 or 4 leukopenia (70%), granulocytopenia (65%), gastrointestinal effects (12%), thromombocytopenia (9%). No data provided for 32P group Less than 1% of women receiving chemotherapy had Grade 3 or 4 myelosuppression. One woman in the 32P group had intestinal occlusion No Grade 3 or 4 adverse events with chemotherapy. One woman in 32P group had pulmonary embolism 20% of women had severe myelosuppression with chemotherapy, no severe adverse events reported in 32P group
NR NR
No treatment-related mortality
NR
NR
NR
P: radioactive chromic phosphate; CT: chemotherapy; NR: not reported; RT: radiotherapy; WAR: whole abdominopelvic radiotherapy.
326
Evidence-based Oncology
Method notes
Search method
Adequate
Selection criteria Adequate: inclusion and exclusion criteria clearly specified Assessment of study quality
Not adequate: unclear if studies assessed for quality. Most studies used
Data synthesis
Adequate: benefits data were extracted from the papers for stage I women and pooled where appropriate. Individual patient data were not available. Measurement scales for adverse events were not reported by the RCTs, so a meta-analysis could not be carried out
Heterogeneity
No significant heterogeneity was found in the meta-analysis
Analysis
The review did not assess publication bias. The more conservative random effects model was used for meta-analysis in preference to the less conservative fixed effects model
Sources of funding: The Cancer Care Ontario Practice Guidelines Initiative’s Gynecology Cancer Disease Site Group and the Ontario Ministry of Health and Long-Term Care. For correspondence: Laurie Elit, MD, Division of Gynecologic Oncology, Juravinski Regional Centre, 699 Concession St, Hamilton, Ont., Canada L8V 5C2. Fax +905 575 6343; E-mail: Laurie.Elit@ hrcc.on.ca. Abstract provided by Bazian Ltd., London.
Commentary This systematic review by Elit et al. concludes that adjuvant platinum-based chemotherapy for women with stage I ovarian carcinoma improves survival and it recommends that all women with stage I ovarian carcinoma who have not been comprehensively surgically staged should be offered platinum-based chemotherapy. Women who have been adequately staged and are found to have stage 1a or 1b disease do not require
adjuvant chemotherapy. In terms of early ovarian cancer management, this review does not offer any new insights but does confirm existing thoughts on the management of early ovarian cancer. The topic is an important one because the majority of women who survive ovarian cancer come from the minority of cases that are diagnosed early; when the tumour has remained confined to the primary ovarian site. Such tumours are associated with a relapse rate of around 20% but the risk for any given individual is largely dependent on the adequacy of surgical staging; an issue that the authors quite correctly emphasise as being crucial. Trials of early ovarian cancer have been conducted for over 30 years but some of these used whole abdominal radiotherapy and non-platinum chemotherapy – forms of treatment that are now considered rather historical in terms of optimal treatment. Nevertheless, the authors have quite correctly included such trials in their review in order to determine whether any effectiveness could be identified. Three major problems have bedevilled trials in this area; most have been too small, most have lacked comprehensive surgical staging and, in general, the trials are rather flawed in design, making meta-analysis difficult. The authors conducted a comprehensive survey of published trials and there are no significant omissions. They used appropriate criteria to select the trials most suitable for the pooled analysis they performed, and they included an instructive tabulation of surgical pathological data that were available from the principal trials prior to randomisation. The review also included a summary of the toxicity and adverse effects reported for the different forms of treatment used in the trials. The principal quantitative result of the review was that adjuvant chemotherapy is associated with reduction in disease recurrence (relative risk 0.70; 95% Cl 0.58 to 0.86; P = 0.0004) and with an improved overall 5-year survival (an absolute difference of 8%; hazard ratio 0.67; 95% Cl 0.50 to 0.90; P = 0.008). The evidence base for this derives largely from the two most recent trials, namely ICON11 and ACTION.2 ACTION2 suggested that chemotherapy would improve survival but that this improvement was confined to the group not adequately surgically staged, suggesting that chemotherapy was impacting on occult metastases not identified at the original surgery. ICON11 also confirmed a survival benefit but its protocol did not include surgical staging.
Evidence-based Oncology Surprisingly, Elit et al. did not include in their discussion a previous systematic review by Winter-Roach et al. published in 2003,3 which came to exactly the same conclusion; that platinum chemotherapy should be offered in early ovarian cancer, except for those in whom adequate surgical staging has revealed encapsulated well-differentiated disease confined to one or both ovaries. The calculated benefit of chemotherapy from this latter review was overall survival with a hazard ratio for overall survival of 0.71 and disease-free survival with a hazard ratio of 0.68, almost identical to that calculated by Elit et al. The bottom line seems to be that early ovarian cancer needs be adequately surgically staged if we are to make confident recommendations for individual treatment. Chemotherapy is not required for encapsulated stages 1a and 1b well differentiated tumours which have been adequately staged. Otherwise chemotherapy is recommended. With regard to optimal regimens to be used, this should probably be the same chemotherapy that would be recommended for advanced disease; the internationally accepted standard of care being carboplatin/paclitaxel. The issues to be addressed by future trials are not clear. Biomarkers such as ploidy and p53 expression have been claimed to have potential value as predictive markers and these could form translational elements of a clinical trial. What is clear is that future trials need to be adequately
327 powered, which will require international collaboration. Quality assessment (1 = fair; 4 = excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
4 4 3 4 3 3
Henry C. Kitchener MD University of Manchester Manchester, UK
References 1. Colombo N, Guthrie D, Chiari S, et al. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst 2003;95:125–32. 2. Trimbos JB, Vergote I, Bolis G, et al. Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 2003;95:113–25. 3. Winter-Roach B, Hooper L, Kitchener H. Systematic review of adjuvant therapy for early stage (epithelial) ovarian cancer. Int J Gynaecol Cancer 2003;13:395–404.
www.elsevierhealth.com/journals/ctrv
EVIDENCE-BASED ONCOLOGY
Adjuvant chemotherapy improves survival after resection of stage 1 ovarian cancer Abstracted from: Elit L, Chambers A, Fyles A, Covens A, Carey M, Fung MFK. Systematic review of adjuvant care for women with stage I ovarian carcinoma. Cancer 2004;101:1926–1935.
Background Approximately one third of women with ovarian cancer have stage 1 disease, which is confined to the ovary. Adjuvant chemotherapy is the standard procedure for women with higher stage disease, but there is uncertainty about the clinical effectiveness of adjuvant therapy for stage 1 disease.
ogy proceedings from 1997 to 2003 and of reference lists of retrieved papers were also carried out.
Inclusion criteria
Objective
Randomised controlled trials (RCTs) comparing two or more adjuvant therapies in women with resected stage 1 ovarian cancer (or including at least 60% of women with stage 1 cancer) were included. Non-English studies were excluded.
To assess the clinical effectiveness of adjuvant therapy in women with resected stage 1 ovarian cancer.
Main outcomes Overall survival; disease-free survival; adverse events.
Method Systematic review with meta-analysis.
Search strategy MEDLINE, CANCERLIT, The Cochrane Collection, Physician Data Query, Canadian Medical Association, and National Guidelines Clearinghouse databases from 1965 to April 2004. Hand searches of American Society of Clinical Oncol-
Main results The review identified 13 RCTs in women with resected stage I ovarian cancer. However, only two RCTs used optimal methods of surgical staging. Adjuvant chemotherapy. Seven RCTs compared adjuvant chemotherapy versus no adjuvant chemotherapy, and five were meta-analysed. Adjuvant chemotherapy significantly reduced death and
0305-7372/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2005.04.003
324
Evidence-based Oncology
disease recurrence compared with no treatment (Evidence Profile: Benefits 1). Two RCTs published as abstracts found no significant difference between different chemotherapy schedules or administration methods (Evidence Profile: Benefits 2). Adjuvant radiotherapy. One small and potentially underpowered RCT found no difference in survival between adjuvant radiotherapy and no treatment. However, one RCT found that adjuvant radiotherapy increased disease recurrence. Adjuvant chemotherapy vs. adjuvant radiotherapy. Three RCTs found no significant difference in survival between adjuvant chemotherapy and pelvic radiotherapy or whole abdominopelvic radiotherapy. One of the RCTs found that adjuvant melphalan significantly increased recurrence-free survival compared with adjuvant pelvic radiotherapy. Four RCTs found no significant difference in overall survival or disease-free survival between
adjuvant chemotherapy and radioactive chromic phosphate. Adverse events and treatment related mortality. Data on adverse events and treatment related mortality were limited and did not allow for comparison across studies (Evidence Profile: Harms).
Authors’ conclusions Overall, adjuvant chemotherapy improves survival and reduces recurrence in women with stage 1 ovarian cancer. However, the extent to which this finding is generalisable to women receiving optimal surgical staging is unclear. There was insufficient evidence on which to draw conclusions on the benefits of adjuvant radiotherapy.
Evidence Profile: Benefits 1 Outcome Death Disease recurrence
Absolute risk Adjuvant chemotherapy
No treatment
95/630 (15.1%) 129/630 (20.5%)
127/621 (20.5%) 181/615 (29.4%)
Relative risk
95% CI
P-Value
0.74 0.70
0.58 to 0.94 0.58 to 0.86
0.01 0.0004
Meta-analysis of five RCTs.
Evidence Profile: Benefits 2 Comparison Different types of chemotherapy Paclitaxel + carboplatin: 3 cycles vs. 6 cycles (n = 321) Intravenous vs. oral chemotherapy (n = 96) Radiotherapy vs. no radiotherapy Pelvic RT vs. no RT (n = 41) Pelvic RT vs. no RT (n = 52) Chemotherapy vs. radiotherapy Cisplatin vs. WAR (n = 70) Chemotherapy vs. pelvic RT (n = 65) Melphalan vs. pelvic RT (n = 57) Cyclophosphamide + cisplatin vs. 32P (n = 251) Cisplatin vs. 32P (n = 161) Cisplatin vs. 32P (n = 340) Meplhalan vs. 32P (n = 141) 32
5-Year disease free survival
P-Value
5-Year overall survival
P-Value
73% vs. 81%
Not significant
NR
NR
NR
Not significant
NR
Not significant
NR 70% vs. 83%
NR P < 0.05
NR NR
Not significant NR
74% vs. 50% NR 94% vs. 70% 70% vs. 76%a
P = 0.07 NR P < 0.05 Not significant
71% vs. 53% 74% vs. 87% NR 81% vs. 79%
P = 0.16 Not significant NR Not significant
NR 79% vs. 82% 80% vs. 80%
NR Not significant Not significant
81% vs. 79% NR 81% vs. 78%
Not significant NR P = 0.48
P: radioactive chromic phosphate; NR: not reported; RT: radiotherapy; WAR: whole abdominopelvic radiotherapy. 10-year recurrence free survival.
a
Evidence-based Oncology
325
Evidence Profile: Harms Comparison
Adverse events
Chemotherapy vs. no chemotherapy Melphalan vs. no CT (n = 81) Mild to moderate haematologic and gastrointestinal toxicity with melphalan. Melphalan associated with myelosuppression (79%), and severe thrombocytopenia (18%) Chemotherapy vs no CT NR (n = 75) Different types of chemotherapy Paclitaxel + carboplatin: Greater toxicity (anaemia, 3 cycles vs. 6 cycles (n = 321) granulocytopenia, neurotoxicity) with 6 cycles of chemotherapy (no further data provided) Intravenous vs. oral Greater toxicity chemotherapy (n = 96) (myelosuppression, GI sequelae, hair loss) with intravenous chemotherapy (no further data provided) Radiotherapy vs. no radiotherapy Pelvic RT vs. no RT (n = 41) Radiotherapy was associated with myelosuppression (66%), bowel cramps/diarrhoea (64%), nausea/ vomiting (54%) and neutropenia (45%) Chemotherapy vs. radiotherapy Cisplatin vs. WAR (n = 70)
Chemotherapy vs. pelvic RT (n = 65) Melphalan vs. pelvic RT (n = 57) Cyclophosphamide + cisplatin vs. 32P (n = 251)
Cisplatin vs.
32
P (n = 161)
Cisplatin vs.
32
P (n = 340)
Meplhalan vs.
32
32
P (n = 141)
Treatment-related mortality NR
No treatment-related mortality
NR
NR
1 surgery-related death in radiotherapy group (no further data provided)
Grade 3 or 4 nausea/vomiting: 71% vs. 14% (P < 0.01). No other Grade 3 or 4 toxicities with chemotherapy. WAR was associated with Grade 3 or 4 diarrhoea (28%) and enteritis (14%) NR
NR
NR Chemotherapy associated with Grade 3 or 4 leukopenia (70%), granulocytopenia (65%), gastrointestinal effects (12%), thromombocytopenia (9%). No data provided for 32P group Less than 1% of women receiving chemotherapy had Grade 3 or 4 myelosuppression. One woman in the 32P group had intestinal occlusion No Grade 3 or 4 adverse events with chemotherapy. One woman in 32P group had pulmonary embolism 20% of women had severe myelosuppression with chemotherapy, no severe adverse events reported in 32P group
NR NR
No treatment-related mortality
NR
NR
NR
P: radioactive chromic phosphate; CT: chemotherapy; NR: not reported; RT: radiotherapy; WAR: whole abdominopelvic radiotherapy.
326
Evidence-based Oncology
Method notes
Search method
Adequate
Selection criteria Adequate: inclusion and exclusion criteria clearly specified Assessment of study quality
Not adequate: unclear if studies assessed for quality. Most studies used
Data synthesis
Adequate: benefits data were extracted from the papers for stage I women and pooled where appropriate. Individual patient data were not available. Measurement scales for adverse events were not reported by the RCTs, so a meta-analysis could not be carried out
Heterogeneity
No significant heterogeneity was found in the meta-analysis
Analysis
The review did not assess publication bias. The more conservative random effects model was used for meta-analysis in preference to the less conservative fixed effects model
Sources of funding: The Cancer Care Ontario Practice Guidelines Initiative’s Gynecology Cancer Disease Site Group and the Ontario Ministry of Health and Long-Term Care. For correspondence: Laurie Elit, MD, Division of Gynecologic Oncology, Juravinski Regional Centre, 699 Concession St, Hamilton, Ont., Canada L8V 5C2. Fax +905 575 6343; E-mail: Laurie.Elit@ hrcc.on.ca. Abstract provided by Bazian Ltd., London.
Commentary This systematic review by Elit et al. concludes that adjuvant platinum-based chemotherapy for women with stage I ovarian carcinoma improves survival and it recommends that all women with stage I ovarian carcinoma who have not been comprehensively surgically staged should be offered platinum-based chemotherapy. Women who have been adequately staged and are found to have stage 1a or 1b disease do not require
adjuvant chemotherapy. In terms of early ovarian cancer management, this review does not offer any new insights but does confirm existing thoughts on the management of early ovarian cancer. The topic is an important one because the majority of women who survive ovarian cancer come from the minority of cases that are diagnosed early; when the tumour has remained confined to the primary ovarian site. Such tumours are associated with a relapse rate of around 20% but the risk for any given individual is largely dependent on the adequacy of surgical staging; an issue that the authors quite correctly emphasise as being crucial. Trials of early ovarian cancer have been conducted for over 30 years but some of these used whole abdominal radiotherapy and non-platinum chemotherapy – forms of treatment that are now considered rather historical in terms of optimal treatment. Nevertheless, the authors have quite correctly included such trials in their review in order to determine whether any effectiveness could be identified. Three major problems have bedevilled trials in this area; most have been too small, most have lacked comprehensive surgical staging and, in general, the trials are rather flawed in design, making meta-analysis difficult. The authors conducted a comprehensive survey of published trials and there are no significant omissions. They used appropriate criteria to select the trials most suitable for the pooled analysis they performed, and they included an instructive tabulation of surgical pathological data that were available from the principal trials prior to randomisation. The review also included a summary of the toxicity and adverse effects reported for the different forms of treatment used in the trials. The principal quantitative result of the review was that adjuvant chemotherapy is associated with reduction in disease recurrence (relative risk 0.70; 95% Cl 0.58 to 0.86; P = 0.0004) and with an improved overall 5-year survival (an absolute difference of 8%; hazard ratio 0.67; 95% Cl 0.50 to 0.90; P = 0.008). The evidence base for this derives largely from the two most recent trials, namely ICON11 and ACTION.2 ACTION2 suggested that chemotherapy would improve survival but that this improvement was confined to the group not adequately surgically staged, suggesting that chemotherapy was impacting on occult metastases not identified at the original surgery. ICON11 also confirmed a survival benefit but its protocol did not include surgical staging.
Evidence-based Oncology Surprisingly, Elit et al. did not include in their discussion a previous systematic review by Winter-Roach et al. published in 2003,3 which came to exactly the same conclusion; that platinum chemotherapy should be offered in early ovarian cancer, except for those in whom adequate surgical staging has revealed encapsulated well-differentiated disease confined to one or both ovaries. The calculated benefit of chemotherapy from this latter review was overall survival with a hazard ratio for overall survival of 0.71 and disease-free survival with a hazard ratio of 0.68, almost identical to that calculated by Elit et al. The bottom line seems to be that early ovarian cancer needs be adequately surgically staged if we are to make confident recommendations for individual treatment. Chemotherapy is not required for encapsulated stages 1a and 1b well differentiated tumours which have been adequately staged. Otherwise chemotherapy is recommended. With regard to optimal regimens to be used, this should probably be the same chemotherapy that would be recommended for advanced disease; the internationally accepted standard of care being carboplatin/paclitaxel. The issues to be addressed by future trials are not clear. Biomarkers such as ploidy and p53 expression have been claimed to have potential value as predictive markers and these could form translational elements of a clinical trial. What is clear is that future trials need to be adequately
327 powered, which will require international collaboration. Quality assessment (1 = fair; 4 = excellent) Relevance Validity Applicability Feasibility Impact Knowledge context
4 4 3 4 3 3
Henry C. Kitchener MD University of Manchester Manchester, UK
References 1. Colombo N, Guthrie D, Chiari S, et al. International Collaborative Ovarian Neoplasm trial 1: a randomized trial of adjuvant chemotherapy in women with early-stage ovarian cancer. J Natl Cancer Inst 2003;95:125–32. 2. Trimbos JB, Vergote I, Bolis G, et al. Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 2003;95:113–25. 3. Winter-Roach B, Hooper L, Kitchener H. Systematic review of adjuvant therapy for early stage (epithelial) ovarian cancer. Int J Gynaecol Cancer 2003;13:395–404.